Researchers enrolling patients with PCS in trials

Primary sclerosing cholangitis (PSC) is a liver disease characterized by the progressive destruction of intra- and extrahepatic bile ducts. It most often occurs in patients with inflammatory bowel disease (IBD) — mainly ulcerative colitis — but is also seen in patients without IBD. PSC can have a variable natural history, but in many patients it is chronic and progressive, eventually leading to biliary cirrhosis, end-stage liver failure and ultimately liver transplantation.

The cause of PSC is unknown, and no medical treatment has proved effective for it. Ursodeoxycholic acid (UDCA), though widely used, is not approved by the Food and Drug Administration (FDA) for PSC, and studies have found it does not improve survival or risk of liver transplantation.

In 2008, a multicenter, randomized controlled trial of high-dose UDCA initiated by Mayo Clinic investigators was discontinued early due to futility. Although patients receiving UDCA showed improved serum liver tests, they had twice the risk of death, liver transplantation and serious adverse events compared with patients receiving placebo. Study results were published in Hepatology in 2009.

In the absence of proven or FDA-approved medical therapy, many providers continue to prescribe low to moderate doses of UDCA. Although patients with normalized liver tests are known to do better, there just isn't enough information to recommend this practice, says Keith D. Lindor, M.D., executive vice provost and dean of the College of Health Solutions at Arizona State University in Phoenix, a hepatologist at Mayo Clinic's Arizona campus and first author of the 2009 study.

He explains: "Part of the problem in finding effective agents for PSC is that we're operating under the assumption that we can find a single cause, but that may not be right. There may be a variety of causative factors, so the aim should be to find drugs with different mechanisms of action. Seeing the response to a therapy can help us better understand causation.

"For instance, about 10 percent of patients with typical PSC have elevated immunoglobulin G4 (IgG4) levels. These patients may have more aggressive disease as suggested by higher Mayo risk scores and abnormal liver test results. They are more likely to respond to immunosuppressants than other PSC patients, so we think this is probably a specific subtype — IgG4-associated cholangitis — requiring a different treatment. Thus, there is an interplay between therapeutic trials and the understanding of pathogenesis."

PSC clinical trials

To further that understanding, Dr. Lindor and colleagues at Mayo Clinic are evaluating four agents that show some promise for treatment of PSC. They include:


VSL#3 is a probiotic typically used in the management of ulcerative colitis and irritable bowel syndrome. "This trial will look at the clinical effects of altering the composition of the gut microbiome and, by extension, the metabolome. In some studies, vancomycin and metronidazole have been used to manipulate the gut flora; this is a less drastic approach," explains Elizabeth J. Carey, M.D., a hepatologist at Mayo Clinic's campus in Phoenix, who is overseeing the trials. The 12-week, open-label study is scheduled to begin enrolling patients in the fall of 2015.

Obeticholic acid

Obeticholic acid is a selective farnesoid X nuclear receptor agonist whose mechanism of action differs from that of UDCA. "We're interested in obeticholic acid because in a phase III trial, it produced significant improvements in patients with primary biliary cirrhosis who didn't respond to UDCA," Dr. Lindor explains. Mayo Clinic's campus in Arizona is participating in an international, multicenter, 24-week, placebo-controlled trial.


Vedolizumab is a humanized monoclonal antibody developed for use in patients with IBD. It inhibits adhesion and migration of leukocytes into the gastrointestinal tract by preventing the alpha-4-beta-7 integrin subunit from binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1). "We're looking at the drug more closely because there has been some evidence of response in IBD patients with liver problems," Dr. Carey says.


Curcumin is the principal compound in the spice, turmeric, which has been shown to have anti-inflammatory and antioxidant properties. This open-label trial is recruiting patients at Mayo Clinic campuses in Phoenix and Rochester, Minnesota.

"The four trials will be sequenced, so we will have a continuous flow of studies. Referring providers can send patients to Dr. Carey, and she will find a trial to put them in," Dr. Lindor says.

"Without the help of referring providers, we won't be able to do these studies," Dr. Carey points out. "Our role is to develop, conduct and report on the trials, but we need other providers to send us patients to enroll in them."

For more information

Contact Dr. Carey at

Lindor KD, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50:808.